The overall objective of this application is to better understand the molecular mechanism of cardiovascular disease that are modified by environmental pollutants. The investigator's models of environmental toxicity will be diesel and gasoline emissions. The underlying hypothesis of this work is that transcriptional regulation in response to these emissions will identify genes that are important in the development of pollution-related cardiovascular disease. Their primary goal is to determine the transcriptional response to complex emissions and the secondary goal is to evaluate any synergistic effect of hypercholesterolemia on this process. Thus, this project will have two specific aims: Specific Aim 1: To define the transcriptional response to whole-exhaust emissions in monocytes and endothelial cells in vivo. Our hypothesis is that the different chemical make-up of diesel exhaust and coal emissions will elicit varied transcriptional responses in endothelial cells and monocytes. We will conduct exposures at two concentrations and with both acute (3 day) and chronic (6 week) duration. Specific Aim 2: To determine the interaction of hypercholesterolemia with inhaled pollutants on gene regulation in these cells. Our hypothesis is that whole exhaust will elicit transcriptional pathways relevant to the formation of atherosclerotic vascular disease, and that these effects will be more substantial in a susceptible model. We will therefore expose control and ApoE -/- mice, on a atherosclerotic diet, to low levels of whole exhaust for 6 weeks. We will use thorough transcriptional analysis to identify genes that are regulated in response to emission, in a novel mouse model that permits assessment of in vivo endothelial responses. They expect that these studies will generate an understanding of the mechanism of exhaust-related cardiovascular morbidity and identify the most important components of whole exhaust that cause such morbidity. They further anticipate that these insights will enhance our understanding of vascular pathology and potentially direct efforts at reducing the toxicity of combustion exhaust.